Publications by authors named "Jaana Hagström"

147 Publications

Additive Manufacturing of Resected Oral and Oropharyngeal Tissue: A Pilot Study.

Int J Environ Res Public Health 2021 Jan 21;18(3). Epub 2021 Jan 21.

Department of Otorhinolaryngology-Head and Neck Surgery, HUS Helsinki University Hospital, University of Helsinki, P.O.Box 263, FI-00029 HUS Helsinki, Finland.

Better visualization of tumor structure and orientation are needed in the postoperative setting. We aimed to assess the feasibility of a system in which oral and oropharyngeal tumors are resected, photographed, 3D modeled, and printed using additive manufacturing techniques. Three patients diagnosed with oral/oropharyngeal cancer were included. All patients underwent preoperative magnetic resonance imaging followed by resection. In the operating room (OR), the resected tissue block was photographed using a smartphone. Digital photos were imported into Agisoft Photoscan to produce a digital 3D model of the resected tissue. Physical models were then printed using binder jetting techniques. The aforementioned process was applied in pilot cases including carcinomas of the tongue and larynx. The number of photographs taken for each case ranged from 63 to 195. The printing time for the physical models ranged from 2 to 9 h, costs ranging from 25 to 141 EUR (28 to 161 USD). Digital photography may be used to additively manufacture models of resected oral/oropharyngeal tumors in an easy, accessible and efficient fashion. The model may be used in interdisciplinary discussion regarding postoperative care to improve understanding and collaboration, but further investigation in prospective studies is required.
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http://dx.doi.org/10.3390/ijerph18030911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908081PMC
January 2021

Three-Dimensional Presentation of Tumor Histopathology: A Model Using Tongue Squamous Cell Carcinoma.

Diagnostics (Basel) 2021 Jan 12;11(1). Epub 2021 Jan 12.

Department of Otorhinolaryngology-Head and Neck Surgery, Helsinki University Hospital and University of Helsinki, 00029 HUS Helsinki, Finland.

Medical imaging often presents objects in three-dimensional (3D) form to provide better visual understanding. In contrast, histopathology is typically presented as two-dimensional (2D). Our objective was to present the tumor dimensions in 3D by creating a 3D digital model of it and so demonstrate the location of the tumor and the histological slices within the surgical soft tissue resection specimen. We developed a novel method for modeling a tongue squamous cell carcinoma using commonly available instruments. We established our 3D-modeling method by recognizing and solving challenges that concern the selection of the direction of histological slices. Additional steps to standard handling included scanning the specimen prior to grossing and modeling the carcinoma, which required only a table scanner and modeling software. We present challenges and their solutions in modeling the resection specimen and its histological slices. We introduce a finished 3D model of a soft tissue resection specimen and the actual tumor as well as its histopathological grossing sites in 3D digital and printed form. Our novel method provides steps to create a digital model of soft tissue resection specimen and the tumor within. To our knowledge, this is the first attempt to present histopathological margins of a tongue tumor in 3D form, whereas previously, only 2D has been available. The creation of the 3D model does not call for predetermined grossing directions for the pathologist. In addition, it provides a crucial initiative to enhance oncological management. The method allows a better visual understanding of tumor margins, topography, and orientation. It thus provides a tool for an improved postoperative assessment and aids, for example, in the discussion of the need for additional surgery and adjuvant therapy.
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http://dx.doi.org/10.3390/diagnostics11010109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827352PMC
January 2021

Active matrix metalloproteinase-8 and interleukin-6 detect periodontal degeneration caused by radiotherapy of head and neck cancer: a pilot study.

Expert Rev Proteomics 2020 10 7;17(10):777-784. Epub 2021 Jan 7.

Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki University Hospital , Helsinki, Finland.

: This cohort study investigated the role of the active matrix metalloproteinase-8 (aMMP-8) and interleukin-6 (IL-6) as oral fluid biomarkers for monitoring the periodontal degeneration occurring in head and neck cancer (HNC) patients treated by radiotherapy. : Eleven patients, aged 28-74, diagnosed with HNC were included in the study. Complete periodontal and oral examinations were performed pre-radiotherapy and 1 month after radiotherapy. Mouthrinse samples (pre-radiotherapy, after 6 weeks of radiotherapy and 1 month after radiotherapy) were assayed by aMMP-8 point-of-care-kit (PerioSafe®/ORALyzer®) for aMMP-8 and ELISA for IL-6. : HNC radiotherapy had a deteriorating impact on the periodontium and a significant impact on periodontal biomarkers aMMP-8 and IL-6 and increased their levels in mouthrinse. Clinical-attachment-loss (CAL) (site of greatest loss: mean = 1.7 mm, range = 1-3 mm) corresponding to rapid progression of periodontitis. There was a positive repeated measures correlation (rmcorr = 0.667) between the aMMP-8 and IL-6 levels. : Elevated aMMP-8 levels were observed 1 month after radiotherapy among some HNC patients suggesting a prolonged increased susceptibility to further periodontal tissue destruction. Currently available aMMP-8 point-of-care testing could be useful to monitor and assess quantitatively online and real-time the risk of deterioration of periodontal health during HNC radiotherapy.
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http://dx.doi.org/10.1080/14789450.2020.1858056DOI Listing
October 2020

Matrix metalloproteinase-7, -8, -9, -15, and -25 in minor salivary gland adenoid cystic carcinoma.

Pathol Res Pract 2021 Jan 22;217:153293. Epub 2020 Nov 22.

Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Oral Pathology and Radiology, University of Turku, Turku University Hospital, Turku, Finland; Research Programs Unit, Translational Cancer Biology Program, University of Helsinki, Helsinki, Finland.

Knowledge on the role of matrix metalloproteinases (MMPs) in adenoid cystic carcinoma (ACC) is limited. MMPs are capable of degrading almost all extracellular and pericellular components to promote invasion and metastasis. This study aimed to evaluate the immunohistochemical expression of MMP-7, -8, -9, -15, and -25 in ACC and to relate the results with clinicopathological factors and survival. The study included 68 patients with minor salivary gland ACC treated at the Helsinki University Hospital (Helsinki, Finland) in 1974-2012. Samples from 52 patients were available, consisting of 44 primary tumours and eight recurrent tumours. We scored immunostaining of MMP-7, -8, -9, -15, and -25 and analysed the immunoscore against clinical and pathological parameters using statistical correlation test. MMP-9 immunoexpression in pseudocysts of ACC and in peritumoural inflammatory cells associated with better survival and fewer treatment failures. High tumoural MMP-7 and -25 associated with better survival. High tumoural MMP-15 associated with poorer survival and high tumoural MMP-9 with advanced stage and regional recurrences. Tumour cells did not show MMP-8 immunopositivity. These results suggest that MMP-9 may contribute to ACC carcinogenesis in different roles. MMP-7, -8, and -9 can stimulate signalling pathways that may promote tissue modulation and metastatic potential. MMP-15 and -25 may reflect prognosis.
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http://dx.doi.org/10.1016/j.prp.2020.153293DOI Listing
January 2021

TKTL1 as a Prognostic Marker in Pancreatic Ductal Adenocarcinoma and Its Correlation with FDG-PET-CT.

Oncology 2021 29;99(3):177-185. Epub 2020 Oct 29.

Department of Gastrointestinal Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Introduction: Glucose metabolism in cancer cells differs from noncancerous cells. The expression of transketolase-like protein 1 (TKTL1), a key enzyme in the glucose metabolism of cancer cells, predicts poor prognosis in several cancer types. We studied TKTL1 as a prognostic tool and whether TKTL1 expression correlates with 18F-FDG-PET-CT among patients with pancreatic ductal adenocarcinoma (PDAC).

Methods: This retrospective study examined two PDAC patient cohorts: 168 patients operated on at Helsinki University Hospital between 2001 and 2011, and 20 patients with FDG-PET-CT results available from the Auria Biobank. We used immunohistochemistry for TKTL1 expression, combining results with clinicopathological data.

Results: Five-year disease-specific survival (DSS) was slightly but not significantly better in patients with a high versus low TKTL1 expression, with DSS of 28.0 versus 17.3%, respectively (p = 0.123). TKTL1 served as a marker of a better prognosis in patients over 65 years old (p = 0.012) and among those with TNM class M1 (p = 0.018), stage IV disease (p = 0.027), or perivascular invasion (p = 0.008).

Conclusions: Our study shows that TKTL1 cannot be used as a prognostic factor in PDAC with the exception of elderly patients and those with advanced disease. The correlation of TKTL1 with 18F-FDG-PET-CT requires further study in a larger patient cohort.
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http://dx.doi.org/10.1159/000510862DOI Listing
October 2020

High Expression of MMP-9 in Primary Tumors and High Preoperative MPO in Serum Predict Improved Prognosis in Colorectal Cancer with Operable Liver Metastases.

Oncology 2021 7;99(3):144-160. Epub 2020 Oct 7.

Transplantation and Liver Surgery, Abdominal Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Introduction: The liver metastases of colorectal cancer (CRC) can be surgically treated in selected cases, with continuously improving results. Matrix metalloproteinases (MMPs) contribute to cancer invasion by degrading the extracellular matrix, and elevated levels of MMP-2, MMP-8, and MMP-9 have been detected in several malignancies. Myeloperoxidase (MPO) is a mediator of tissue damage that can oxidatively activate latent MMPs. We evaluated the prognostic value of MMP-2, MMP-8, and MMP-9 in tissue samples of primary tumors and liver metastases and the pre- and postoperative serum levels of MMP-8, MMP-9, and MPO in CRC patients undergoing liver resection.

Methods: Tissue and serum samples were obtained from 111 patients who had primary colorectal tumors and their liver metastases surgically treated at the Helsinki University Hospital between 1988 and 2007. Tissue expression of MMP-2, MMP-8, and MMP-9 in primary tumors and liver metastases was evaluated by immunohistochemistry. Pre- and postoperative serum concentrations of MMP-8, MMP-9, and MPO were determined using a time-resolved immunofluorometric assay or commercially available enzyme-linked immunosorbent assay kits. Clinical data were retrieved from patient records and the Central Statistical Office of Finland. Associations with disease-free survival (DFS) and overall survival (OS) were estimated using Cox regression analysis and the Kaplan-Meier method.

Results: High expression of MMP-9 in colorectal tumor tissue was associated with better DFS (p = 0.010), and high preoperative MPO in serum with improved DFS and OS (p < 0.001 and p = 0.014, respectively). The prognostic significance varied according to gender, age, and the synchronicity of liver metastases.

Conclusion: Low preoperative MPO in serum might identify patients at high risk of recurrence and death after resection of colorectal liver metastases. Elevated preoperative MPO and high expression of MMP-9 in colorectal tumor tissue indicate an improved prognosis. The use of these biomarkers should be adjusted according to clinical characteristics.
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http://dx.doi.org/10.1159/000510609DOI Listing
October 2020

MMP-7, -8, -9, E-cadherin, and beta-catenin expression in 34 ameloblastoma cases.

Clin Exp Dent Res 2021 Feb 28;7(1):63-69. Epub 2020 Sep 28.

Department of Pathology, Haartman Institute, University of Helsinki and HUSLAB, Helsinki, Finland.

Objectives: Ameloblastoma is a benign, locally aggressive odontogenic tumor with high recurrence rates. Matrix metalloproteinases (MMPs) mediate extracellular integrity in normal and pathological conditions, and exert multiple functions coordinating inflammation and tumor progression. E-cadherin and beta-catenin are adherence junction molecules in cell-to-cell connections. We investigated the involvement of MMP-7, -8, -9, E-cadherin, and beta-catenin in ameloblastoma and the surrounding extracellular matrix.

Material And Methods: Our material consisted of 30-34 tissue samples from ameloblastoma patients of Helsinki University Hospital. We used immunohistochemistry to detect the expression of the biomarkers. Two oral pathologists independently scored the immunoexpression intensities and statistical calculations were made based on the results.

Results: E-cadherin expression was weaker in the maxillary than in mandibular ameloblastomas. Beta-catenin was expressed in the ameloblastoma cell membranes. We detected MMP-8 and -9 expression in polymorphonuclear neutrophils in the extracellular area and these MMPs correlated positively with each other. Osteoclasts lining bone margins and multinuclear giant cells expressed MMP-9. Neither MMP-8 nor MMP-9 immunoexpression could be detected in ameloblastoma cells. MMP-7 expression was seen in some apoptotic cells.

Conclusion: The fact that E-cadherin immunoexpression was weaker in maxillary compared to mandibular ameloblastomas might associate to earlier recurrences. It promotes the idea of mandibular and maxillary ameloblastoma exerting differences in their biologies. We detected MMP-8 and -9 in polymorphonuclear neutrophils which relates to these MMPs participating in extracellular remodeling through a mild inflammatory process. Bone degradation around ameloblastoma may be due to MMP-9 in osteoclasts but this phenomenon might be an independent process and needs further investigations.
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http://dx.doi.org/10.1002/cre2.331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853880PMC
February 2021

Stromal categorization in early oral tongue cancer.

Virchows Arch 2020 Sep 21. Epub 2020 Sep 21.

Institute of Biomedicine, Pathology, University of Turku and Turku University Hospital, Turku, Finland.

Stromal categorization has been used to classify many epithelial cancer types. We assessed the desmoplastic reaction and compared its significance with other stromal characteristics in early (cT1-2N0) oral tongue squamous cell carcinoma (OTSCC). In this multi-institutional study, we included 308 cases treated for early OTSCC at five Finnish university hospitals or at the A.C. Camargo Cancer Center in São Paulo, Brazil. The desmoplastic reaction was classified as immature, intermediate, or mature based on the amount of hyalinized keloid-like collagen and myxoid stroma. We compared the prognostic value of the desmoplastic reaction with a stromal grading system based on tumor-stroma ratio and stromal tumor-infiltrating lymphocytes. We found that a high amount of stroma with a weak infiltration of lymphocytes was associated statistically significantly with a worse disease-free survival with a hazard ratio (HR) of 2.68 (95% CI 1.26-5.69), worse overall survival (HR 2.95, 95% CI 1.69-5.15), and poor disease-specific survival (HR 2.66, 95% CI 1.11-6.33). Tumors having a high amount of stroma with a weak infiltration of lymphocytes were also significantly associated with a high rate of local recurrence (HR 4.13, 95% CI 1.67-10.24), but no significant association was found with lymph node metastasis (HR 1.27, 95% CI 0.37-4.35). Categorization of the stroma based on desmoplastic reaction (immature, intermediate, mature) showed a low prognostic value for early OTSCC in all survival analyses (P > 0.05). In conclusion, categorization of the stroma based on the amount of stroma and its infiltrating lymphocytes shows clinical relevance in early OTSCC superior to categorization based on the maturity of stroma.
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http://dx.doi.org/10.1007/s00428-020-02930-5DOI Listing
September 2020

Cell-in-cell phenomenon associates with aggressive characteristics and cancer-related mortality in early oral tongue cancer.

BMC Cancer 2020 Sep 3;20(1):843. Epub 2020 Sep 3.

Institute of Biomedicine, Pathology, University of Turku, Turku, Finland.

Background: Cell-in-cell structures (caused by cell cannibalistic activity) have been related to prognosis of many cancers. This is the first multi-institutional study to assess the prognostic impact of cell-in-cell structures in a large cohort of early oral tongue squamous cell carcinomas (OTSCC).

Methods: A total of 308 cases from five Finnish University Hospitals and from the A.C. Camargo Cancer Center, São Paulo, Brazil, were included in this study. Cell-in-cell structures were evaluated on surgical postoperative sections that stained with hematoxylin and eosin staining.

Results: We found that cell-in-cell structures associated with cancer-related mortality in univariable analysis with a hazard ratio (HR) of 2.99 (95%CI 1.52-5.88; P = 0.001). This association was confirmed in multivariable analysis (HR 2.22, 95%CI 1.12-4.44; P = 0.024). In addition, statistically significant associations were observed between the cell-in-cell structures and other adverse histopathologic characteristics including deep invasion (P <  0.001), high index of tumor budding (P = 0.007), worst pattern of invasion (P <  0.001), perineural invasion (P = 0.01), and stroma-rich pattern (P = 0.001).

Conclusions: Our findings demonstrate a significant relationship between cell-in-cell formation and aggressive characteristics of early OTSCC. Cell-in-cell structures have a distinct impact as a novel prognostic indicator in early OTSCC and they can be easily assessed during routine pathology practice.
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http://dx.doi.org/10.1186/s12885-020-07342-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469910PMC
September 2020

High TKTL1 expression as a sign of poor prognosis in colorectal cancer with synchronous rather than metachronous liver metastases.

Cancer Biol Ther 2020 09 14;21(9):826-831. Epub 2020 Aug 14.

Transplantation and Liver Surgery, Abdominal Center, University of Helsinki and Helsinki University Hospital , Helsinki, Finland.

Colorectal cancer (CRC) is the third most common cancer in the world. More than half of all affected patients develop liver metastases during the course of the disease, and over half experience recurrence despite radical primary surgery. Transketolase-like protein 1 (TKTL1) is a key enzyme in the glucose metabolism of cancer cells, and its expression in tumor tissue was previously shown to indicate a poor prognosis in colorectal cancer. In this study, we investigated the prognostic significance of TKTL1 in 111 patients with surgically resected colorectal liver metastases, with a minimum follow-up time of 10.3 years. TKTL1 expression was examined in tissue samples of both primary tumors and liver metastases, and compared to clinicopathological parameters, disease-free survival, and overall survival. We show that a high expression of TKTL1 in primary tumor tissue associated with poor disease-free survival in patients with synchronous liver metastases ( = .026, Kaplan-Meier log-rank test), but with better disease-free survival in patients with metachronous metastases, although not statistically significantly ( = .073). We found similar tendencies for TKTL1 expression in liver metastases. Thus, TKTL1 could serve as a candidate marker to identify patients who benefit from liver resection or who need more aggressive perioperative chemotherapy.
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http://dx.doi.org/10.1080/15384047.2020.1803008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515493PMC
September 2020

Expression and Role of E-Cadherin, β-Catenin, and Vimentin in Human Papillomavirus-Positive and Human Papillomavirus-Negative Oropharyngeal Squamous Cell Carcinoma.

J Histochem Cytochem 2020 09 14;68(9):595-606. Epub 2020 Aug 14.

Department of Otorhinolaryngology-Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Oropharyngeal squamous cell carcinoma (OPSCC) is subclassified by the World Health Organization into two different entities: human papillomavirus (HPV)-positive and HPV-negative tumors. HPV infection promotes the epithelial-to-mesenchymal transition (EMT) and transformation of keratinocyte stem cells into cancer stem cells. EMT is a crucial process in the carcinogenesis of epithelial-derived malignancies, and we aimed to study the role of its markers in OPSCC. This study consists of 202 consecutive OPSCC patients diagnosed and treated with curative intent. We examined E-cadherin, β-catenin, and vimentin expression using immunohistochemistry and compared these with tumor and patient characteristics and treatment outcome. We found that the cell-membranous expression of β-catenin was stronger in HPV-positive than in HPV-negative tumors, and it was stronger in the presence of regional metastasis. The stromal vimentin expression was stronger among HPV-positive tumors. A high E-cadherin expression was associated with tumor grade. No relationship between these markers and survival emerged. In conclusion, β-catenin and vimentin seem to play different roles in OPSCC: the former in the tumor tissue itself, and the latter in the tumor stroma. HPV infection may exploit the β-catenin and vimentin pathways in carcinogenic process. More, β-catenin may serve as a marker for the occurrence of regional metastasis.
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http://dx.doi.org/10.1369/0022155420950841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469711PMC
September 2020

MRI correlates to histopathological data in oral tongue squamous cell carcinoma diagnostics.

Acta Odontol Scand 2020 Jul 11:1-6. Epub 2020 Jul 11.

HUS Medical Imaging Center, Department of Radiology, Helsinki University Hospital, Helsinki, Finland.

Objectives: The purpose of this study was to compare magnetic resonance imaging (MRI) maximum tumor diameter and depth of invasion with histopathology in oral tongue squamous cell carcinoma (OTSCC) patients in our Institute. Another objective was to compare recorded nodal status between MRI and histology.

Material And Methods: MRI and pathological records of 45 patients diagnosed with T1-T3 OTSCC were reviewed retrospectively. Maximum tumor diameter and depth of invasion were measured and rechecked by oral radiologist and pathologist. Nodal status was recorded from both MRI and histopathology. Correlation analyses were performed using Pearson's correlation.

Results: Both maximum tumor diameter and depth of invasion correlated significantly between MRI and histology ( = 0.874,  < .001;  = 0.898,  < .001). Significant correlation was found between MRI and pathological dimensions in the MRI-based T-staged subgroups of T2 and T3 but not in T1. MRI sensitivity for detecting pathologically positive nodes was 60%. MRI specificity for detecting pathologically negative nodes was 83%. Moderate correlation was found between MRI and histological nodal status ( = 0.44,  = .003).

Conclusions: MRI tumor dimensions correlate with histopathological data in OTSCC. Based on our Finnish patient material and results, MRI serves as an accurate tool in supporting OTSCC patient treatment in our Institute.
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http://dx.doi.org/10.1080/00016357.2020.1789736DOI Listing
July 2020

Additive clinical impact of epidermal growth factor receptor and podocalyxin-like protein expression in pancreatic and periampullary adenocarcinomas.

Sci Rep 2020 06 25;10(1):10373. Epub 2020 Jun 25.

Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Skåne University Hospital, 22185, Lund, Sweden.

The outcome of periampullary adenocarcinomas remains poor with few treatment options. Podocalyxin-like protein (PODXL) is an anti-adhesive protein, the high expression of which has been shown to confer a poor prognosis in numerous malignancies. A correlation and adverse prognostic synergy between PODXL and the epidermal growth factor receptor (EGFR) has been observed in colorectal cancer. Here, we investigated whether this also applies to periampullary adenocarcinomas. We analyzed the immunohistochemical expression of PODXL and EGFR in tissue microarrays with tumors from two patient cohorts; (Cohort 1, n = 175) and (Cohort 2, n = 189). The effect of TGF-β-induced expression and siRNA-mediated knockdown of PODXL and EGFR, were investigated in pancreatic cancer cells (PANC-1) in vitro. We found a correlation between PODXL and EGFR in these cancers, and a synergistic adverse effect on survival. Furthermore, silencing PODXL in pancreatic cancer cells resulted in the down-regulation of EGFR, but not vice versa. Consequently, these findings suggest a functional link between PODXL and EGFR, and the potential combined utility as biomarkers possibly improving patient stratification. Further studies examining the mechanistic basis underlying these observations may open new avenues of targeted treatment options for subsets of patients affected by these particularly aggressive cancers.
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http://dx.doi.org/10.1038/s41598-020-67187-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316735PMC
June 2020

Comparing serum protein levels can aid in differentiating HPV-negative and -positive oropharyngeal squamous cell carcinoma patients.

PLoS One 2020 15;15(6):e0233974. Epub 2020 Jun 15.

Department of Otorhinolaryngology-Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Background: The surrogate immunohistochemical marker, p16INK4a, is used in clinical practice to determine the high-risk human papillomavirus (HPV) status of oropharyngeal squamous cell carcinomas (OPSCC). With a specificity of 83%, this will misclassify some patients compared with direct HPV testing. Patients who are p16INK4a-positive but HPV DNA-negative, or RNA-negative, may be unsuitable for treatment de-escalation aimed at reducing treatment-related side effects. We aimed to identify cost-effective serum markers to improve decision making for patients at risk of misclassification by p16INK4a alone.

Methods: Serum proteins from pre-treatment samples of 36 patients with OPSCC were identified and quantified using label-free mass spectrometry-based proteomics. HPV-status was determined using p16INK4a/HPV DNA and E6/E7 mRNA. Serum protein expressions were compared between groups of patients according to HPV status, using the unpaired t-test with a Benjamini-Hochberg correction. ROC curves (AUC) were calculated with SPSS (v25).

Results: Of 174 serum proteins identified, complement component C7 (C7), apolipoprotein F (ApoF) and galectin-3-Binding Protein (LGALS3BP) significantly differed between HPV-positive and -negative tumors (AUC ranging from 0.84-0.87). ApoF levels were more than twice as high in the E6/E7 mRNA HPV-positive group than HPV-negative.

Conclusions: Serum C7, ApoF and LGALS3BP levels discriminate between HPV-positive and HPV-negative OPSCC. Further studies are needed to validate these host immunity-related proteins as markers for HPV-associated OPSCC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233974PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295232PMC
August 2020

Periodontitis in tonsil cancer patients-A comparative study in accordance with tumour p16 status.

Oral Dis 2020 Nov 19;26(8):1625-1630. Epub 2020 Jun 19.

Department of Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Objectives: We assessed the periodontal situation radiologically according to tumour p16 status.

Materials And Methods: Patients with a diagnosis of tonsillar cancer and availability of a digital panoramic radiograph (DPR) during a 5-year period were included in this retrospective study. The predictor variables were periodontal stability, marginal bone loss, marginal bone loss without periodontal stability and total number of teeth. Periodontal status was compared with p16 status, age, gender, smoking and alcohol use.

Results: Among 115 patients included in the analyses (p16-negative, n = 24; p16-positive, n = 91), smoking (p < .0001), heavy alcohol use (p < .0001) and total number of teeth (p = .0001) were significantly associated with p16 status. Current smoking (OR = 7.3) and heavy alcohol use (OR = 10.1) increased the risk of p16-negative cancer.

Conclusions: Patients with p16-negative tonsillar carcinoma had less teeth than patients with p16-positive tumours. Other periodontal findings were common in both groups without statistical significance. Heavy alcohol use and smoking were the most important risk factors for p16-negative tonsillar carcinoma.
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http://dx.doi.org/10.1111/odi.13437DOI Listing
November 2020

Transketolase-Like Protein 1 and Glucose Transporter 1 in Gastric Cancer.

Oncology 2020 20;98(9):643-652. Epub 2020 May 20.

Department of Gastrointestinal Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Background: The glucose metabolism of cancer cells differs from that of noncancerous cells. Transketolase-like protein 1 (TKTL1) and glucose transporter 1 (GLUT1) both play a role in this process. These biochemical tumor markers are overexpressed in several types of human cancer.

Objective: We sought to determine if TKTL1 and/or GLUT1 expression predicts prognosis in gastric cancer.

Methods: In this retrospective study, we selected 284 patients who underwent surgery for gastric cancer at the Helsinki University Hospital. We used immunohistochemistry to assess the expression of TKTL1 and GLUT1, combined with clinicopathological data.

Results: Positive expression of TKTL1 was associated with positive expression of GLUT1, age over 65 years, male gender, advanced stage (II-IV), and advanced tumors (T2-T4). Patients with a positive expression of TKTL1 had a poorer prognosis than those with no expression (p = 0.042, Breslow test). GLUT1 positivity was associated with higher age and with the intestinal type of gastric cancer but did not carry any prognostic value.

Conclusion: In conclusion, our study showed that positive expression of TKTL1 correlates with a poor prognosis in gastric cancer.
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http://dx.doi.org/10.1159/000507350DOI Listing
September 2020

The prognostic role of tissue TLR2 and TLR4 in colorectal cancer.

Virchows Arch 2020 Nov 19;477(5):705-715. Epub 2020 May 19.

Department of Surgery, University of Helsinki and Helsinki University Hospital HUS, Haartmaninkatu 4, PO Box 440, FIN-00029, Helsinki, Finland.

Colorectal cancer (CRC), the second most common cancer globally, resulted in 881,000 deaths in 2018. Toll-like receptors (TLRs) are crucial to detecting pathogen invasion and inducing the host's immune response. This study aimed to explore the prognostic value of TLR2 and TLR4 tumor expressions in colorectal cancer patients. We studied the immunohistochemical expressions of TLR2 and TLR4 using tissue microarray specimens from 825 patients undergoing surgery in the Department of Surgery, Helsinki University Hospital, between 1982 and 2002. We assessed the relationships between TLR2 and TLR4 expressions and clinicopathological variables and patient survival. We generated survival curves using the Kaplan-Meier method, determining significance with the log-rank test. Among patients with lymph node-positive disease and no distant metastases (Dukes C), a strong TLR2 immunoactivity associated with a better prognosis (p < 0.001). Among patients with local Dukes B disease, a strong TLR4 immunoactivity associated with a worse disease-specific survival (DSS; p = 0.017). In the multivariate survival analysis, moderate TLR4 immunoactivity compared with strong TLR4 immunoactivity (hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.49-0.89, p = 0.007) served as an independent prognostic factor. In the multivariate analysis for the Dukes subgroups, moderate TLR2 immunoactivity (HR 2.63, 95% CI 1.56-4.44, p < 0.001) compared with strong TLR2 immunoactivity served as an independent negative prognostic factor in the Dukes C subgroup. TLR2 and TLR4 might be new prognostic factors to indicate which CRC patients require adjuvant therapy and which could spare from an unnecessary follow-up, but further investigations are needed.
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http://dx.doi.org/10.1007/s00428-020-02833-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581516PMC
November 2020

In HPV-negative oropharyngeal squamous cell carcinoma, elevated toll-like receptor 2 immunoexpression may increase the risk of disease-specific mortality.

Oral Oncol 2020 08 11;107:104778. Epub 2020 May 11.

Department of Pathology, University of Helsinki, HUSLAB and Helsinki University Hospital, P.O. Box 21, 00014 Helsinki, Finland; Research Programs Unit, Translational Cancer Medicine, University of Helsinki, P.O. Box 63, 00014 Helsinki, Finland; Department of Oral Pathology and Radiology, Institute of Dentistry, Faculty of Medicine, University of Turku, Turku, Finland.

Objectives: In oropharyngeal squamous cell carcinoma (OPSCC), toll-like receptors (TLR) 5 and 7 associate with the tumor's human papilloma virus (HPV) status (Jouhi et al., 2017). TLR 2, on the other hand, has been linked to head and neck squamous cell carcinoma (HNSCC), and to oral carcinogenesis (Farnebo et al., 2015; Binder Gallimidi et al., 2015). Here we investigated the presence of TLR 2 and 4 in HPV-positive and HPV-negative OPSCC, and their relationship to opportunistic oral pathogen Treponema denticola chymotrypsin-like protease (Td-CTLP) immunoexpression, clinical parameters, and patient outcome.

Materials And Methods: Clinicopathological data of 198 unselected consecutive OPSCC patients came from hospital registries. Immunoexpression of TLRs 2 and 4 we evaluated by immunohistochemistry, and earlier in this patient series we studied immunoexpression of Td-CTLP and HPV DNA, HPV mRNA, and p16 status.

Results: Immunoexpression of both TLRs 2 and 4 showed a significant association with HPV-status. Strong expression was associated with HPV-positivity and mild expression with HPV-negativity. Patients with strong TLR 2 immunoexpression in the HPV negative subgroup had significantly poorer 5-year DSS (58%) than did patients with mild TLR 2 expression (77%), and strong TLR 2 immunoexpression remained as an independent factor linked to increased disease mortality in the multivariable setting (P = 0.019). No association existed between TLR 2 or 4 and Td-CTLP expression.

Conclusion: Our results support the role of TLR 2 receptor as a possible target for development of therapeutics as earlier proposed (Farnebo et al., 2015). The involvement of Td and other oral pathogens in carcinogenesis of OPSCC, remains open and calls for further study.
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http://dx.doi.org/10.1016/j.oraloncology.2020.104778DOI Listing
August 2020

Association between local immune cell infiltration, mismatch repair status and systemic inflammatory response in colorectal cancer.

J Transl Med 2020 04 21;18(1):178. Epub 2020 Apr 21.

Department of Surgery, University of Helsinki and Helsinki University Hospital, 00114, Helsinki, Finland.

Background: Systemic inflammatory response in colorectal cancer (CRC) has been established as a prognostic factor for impaired cancer-specific survival, predominantly in patients with right-sided tumors. On the other hand, defective mismatch repair (dMMR) tumors, primarily located in the right colon, are known to have favorable survival and dense local immune infiltration. The aim of this study was to see if there is any form of relationship between these seemingly diverse entities.

Methods: Complete clinical and long-term survival data were retrieved for 316 CRC patients operated at Helsinki University Hospital between the years 1998 and 2003. Tissue microarrays were prepared from surgical specimens and further processed and analyzed for local immune cell infiltration using multispectral imaging with a Vectra quantitative pathology imaging system and Inform software. Multiplex immunohistochemistry was applied using antibodies against CD66b, CD8, CD20, FoxP3, CD68 and pan-Cytokeratin. After exclusions, data on immune infiltration were available for 275 patients. Mismatch repair status was determined by immunohistochemistry.

Results: CRP was seen to be an independent predictor of cancer-specific survival but not overall survival in uni- and multivariable (HR 1.01 (1.00-1.02); p = 0.028) analyses of non-irradiated patients. There was no significant difference in CRP according to mismatch repair status, but all cases (n = 10) with CRP ≥ 75 mg/l had proficient mismatch repair (pMMR). There was a significant negative correlation between intratumor stromal infiltration by T-regulatory FOXP3 cells and CRP (p = 0.006). There was significantly lower intratumor stromal infiltration by FOXP3 cells (p = 0.043) in the right colon compared to the rectum, but no significant difference in CRP (p = 0.44). CRP was not a predictor of overall survival (HR 0.99, 95% CI 0.98-1.01) nor cancer-specific survival in irradiated patients (HR 0.94, 95% CI 0.94-1.02).

Conclusions: There was a significant negative relationship between SIR, defined as an elevated CRP, and intratumor stromal infiltration by T-regulatory FOXP3cells. This and the fact that all cases with a CRP > 75 mg/l had pMMR suggests that SIR and dMMR are independent entities in CRC. Indeed, the general lack of difference in CRP between cases with dMMR and pMMR may be evidence of overlap in cases with a less pronounced SIR.
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http://dx.doi.org/10.1186/s12967-020-02336-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175507PMC
April 2020

Epstein-Barr virus (EBV) and polyomaviruses are detectable in oropharyngeal cancer and EBV may have prognostic impact.

Cancer Immunol Immunother 2020 Aug 20;69(8):1615-1626. Epub 2020 Apr 20.

Department of Pathology, University of Helsinki and HUS Helsinki University Hospital, P.O. Box 21, 00014 HUS, Helsinki, Finland.

Background: The etiological role of human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OPSCC) is confirmed. However, the role of other oncoviruses in OPSCC is unknown.

Materials And Methods: A total of 158 consecutive OPSCC patients treated with curative intent were included. DNA extracted from tumor sections was used to detect Epstein-Barr virus (EBV), HPV, and the following polyomaviruses: John Cunningham virus (JCV), Simian virus 40 (SV40), and BK virus (BKV) with PCR. In addition, p16 expression was studied by immunohistochemistry, and EBV-encoded small RNA (EBER) transcripts were localized by in situ hybridization. The effect of viral status on overall survival (OS) and disease-free survival (DFS) was analyzed.

Results: A total of 94/158 samples (59.5%) were HPV-positive, 29.1% contained BKV DNA, 20.3% EBV DNA, 13.9% JCV DNA, and 0.6% SV40 DNA. EBER was expressed only in stromal lymphocytes adjacent to the tumor and correlated with HPV positivity (p = 0.026). p16 expression associated only with HPV. None of the three polyomaviruses had an impact on survival. Patients with EBER-positive but HPV-negative OPSCC had significantly poorer OS and DFS than those with HPV-positive OPSCC and slightly worse prognosis compared with the patients with EBER-negative and HPV-negative OPSCC.

Conclusion: Polyomaviruses are detectable in OPSCC but seem to have no impact on survival, whereas HPV was the strongest viral prognostic factor. EBER expression, as a sign of latent EBV infection, may have prognostic impact among patients with HPV-negative OPSCC. EBER analysis may identify a new subgroup of OPSCCs unrelated to HPV.
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http://dx.doi.org/10.1007/s00262-020-02570-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347695PMC
August 2020

Elevated TLR5 expression in vivo and loss of NF-κΒ activation via TLR5 in vitro detected in HPV-negative oropharyngeal squamous cell carcinoma.

Exp Mol Pathol 2020 06 30;114:104435. Epub 2020 Mar 30.

Department of Pathology, University of Helsinki, HUSLAB and Helsinki University Hospital, P. O. Box 21, 00014 Helsinki, Finland; Department of Surgery, University of Helsinki and Helsinki University Hospital, P. O. Box 20, FI-00014, Helsinki, Finland; Department of Oral Pathology and Radiology, Institute of Dentistry, Faculty of Medicine, University of Turku, Turku, Finland.

In oropharyngeal squamous cell carcinoma (OPSCC), the expression pattern of toll-like receptors (TLRs), in comparison between human papillomavirus (HPV)-positive and -negative tumors differs. TLRs control innate immune responses by activating, among others, the nuclear factor-κΒ (NF-κΒ) signaling pathway. Elevated NF-κΒ activity is detectable in several cancers and regulates cancer development and progression. We studied TLR5 expression in 143 unselected consecutive OPSCC tumors, and its relation to HPV-DNA and p16 status, clinicopathological parameters, and patient outcome, and studied TLR5 stimulation and consecutive NF-κB cascade activation in vitro in two human OPSCC cell lines and immortalized human keratinocytes (HaCat). Clinicopathological data came from hospital registries, and TLR5 immunoexpression was evaluated by immunohistochemistry. Flagellin served to stimulate TLR5 in cultured cells, followed by analysis of the activity of the NF-κB signaling cascade with In-Cell Western for IκΒ and p-IκΒ. High TLR5 expression was associated with poor disease-specific survival in HPV-positive OPSCC, which typically shows low TLR5 immunoexpression. High TLR5 immunoexpression was more common in HPV-negative OPSCC, known for its less-favorable prognosis. In vitro, we detected NF-κΒ cascade activation in the HPV-positive OPSCC cell line and in HaCat cells, but not in the HPV-negative OPSCC cell line. Our results suggest that elevated TLR5 immunoexpression may be related to reduced NF-κΒ activity in HPV-negative OPSCC. The possible prognosis-worsening mechanisms among these high-risk OPSCC patients however, require further evaluation.
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http://dx.doi.org/10.1016/j.yexmp.2020.104435DOI Listing
June 2020

Tetraspanin CD63 independently predicts poor prognosis in colorectal cancer.

Histol Histopathol 2020 Aug 19;35(8):887-892. Epub 2020 Feb 19.

Research Programs Unit, Translational Cancer Biology, University of Helsinki, Helsinki, Finland.

CD63, a member of the tetraspanin family, is expressed in endosomes and enriched in exosomes. Tetraspanins participate in a variety of physiological processes, including cellular differentiation, cell-cell fusion, and cell migration. CD63 reportedly carries both protumorigenic and tumor suppressor properties, and appears to be upregulated in breast cancer, astrocytoma, and melanoma. Yet, the effect of CD63 on cancer prognosis remains unclear, and no previous reports examined it in colorectal cancer (CRC). Identifying novel biomarkers will allow us to better differentiate patients with an increased risk of recurrence and who might benefit from adjuvant therapy. We applied immunohistochemistry with antibodies to human CD63 on 620 consecutive CRC patients treated at the Helsinki University Hospital. We evaluated the associations between CD63 expression and clinicopathological parameters and patient prognosis. We found that CD63 expression associated with an advanced stage, poor differentiation, and mucinous histology. We found no association between CD63 expression and age, sex or tumor location. CD63 expression predicted an unfavorable prognosis in CRC (p=0.00001, log-rank test) and in a subgroup of patients with metastasized CRC (p=0.011). Cox's multivariate analysis identified CD63 as an independent factor predicting an unfavorable prognosis in CRC and in the subgroup with metastasized disease. We show for the first time that CD63 immunohistochemistry expression represents an independent marker of an unfavorable prognosis in CRC and associates with unfavorable clinicopathological parameters. Our results support the hypothesis that a higher tissue expression of CD63 in CRC, indicating an epithelial-to-mesenchymal transition (EMT)-associated secretory phenotype, associated with an adverse outcome.
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http://dx.doi.org/10.14670/HH-18-209DOI Listing
August 2020

Sinonasal Oncocytic Papilloma-A Series of 20 Cases With Special Emphasis on Recurrences.

Laryngoscope Investig Otolaryngol 2019 Dec 30;4(6):567-572. Epub 2019 Sep 30.

Department of Otorhinolaryngology-Head and Neck Surgery University of Helsinki and HUS Helsinki University Hospital Helsinki Finland.

Objective: Reports on sinonasal oncocytic papilloma (SNOP) are scarce. The aim of this retrospective study was to evaluate the clinical features of this rarest form of sinonasal papilloma with special emphasis on the pattern of recurrences and on the potential factors predicting them.

Study Design: Retrospective study.

Methods: Between the years 1994 and 2016, 20 patients (mean age 66 years; range 30-87) were diagnosed with SNOP at the Department of Otorhinolaryngology-Head and Neck Surgery, HUS Helsinki University Hospital (Helsinki, Finland). Hospital charts were reviewed to record various medical and sociodemographic patient characteristics, and the archived histological specimens were re-evaluated. Postoperative follow-up time varied between 26 days and 167 months.

Results: Maxillary sinus was the most common (60%) tumor location. None of the tissue samples showed dysplasia. Recurrence rate was 39% and the median time span to the first recurrence was 25 months (range 7-71). Smokers had more often a recurrence than nonsmokers (75% vs. 31%). Patients with perioperative purulent rhinosinusitis during the primary surgery had a higher recurrence rate compared with those without (60% vs. 31%). Tumors located in the sinuses recurred more often than those located in the nasal cavity (45% vs. 29%). However, all these findings remained statistically nonsignificant. None of the cases showed malignant transformation during the follow-up.

Conclusion: SNOP has a propensity to recur. History of smoking, purulent rhinosinusitis during the primary surgery, and tumor location in the sinuses outside the nasal cavity seem to contribute to an increased trend in the risk of recurrence.

Level Of Evidence: 4.
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http://dx.doi.org/10.1002/lio2.308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929580PMC
December 2019

The Prognostic Importance of CD20 B lymphocytes in Colorectal Cancer and the Relation to Other Immune Cell subsets.

Sci Rep 2019 12 27;9(1):19997. Epub 2019 Dec 27.

Department of Medical Biosciences/Pathology, Umeå University, Umeå, Sweden.

The anti-tumour immune response is critical to patient prognosis in colorectal cancer (CRC). The aim of this study was to investigate infiltration of B lymphocytes into CRC tumours, and their clinical relevance, prognostic value and relation to other immune cell subsets. We used multiplexed immunohistochemistry and multispectral imaging to assay the amount of infiltrating CD20 B lymphocytes along with infiltration of CD8 cytotoxic T cells, FOXP3 T regulatory cells, CD68 macrophages and CD66b neutrophils, in 316 archival CRC tissue specimens. A higher density of infiltrating CD20 B lymphocytes was associated with tumours of the right colon (P = 0.025) and of lower stages (P = 0.009). Furthermore, patients whose tumours were highly infiltrated by CD20 B lymphocytes had a significantly improved disease-specific survival (HR = 0.45, 95% CI 0.28-0.73, P = 0.001), which remained significant in multivariable analysis. CD20 B lymphocytes were highly and positively associated with CD8 T lymphocytes (P < 0.001), and part of the prognostic role was found to be a cooperative effect between these lymphocyte subsets. Our results support a favourable prognostic value of tumour-infiltrating CD20 B lymphocytes in CRC. Furthermore, a cooperative prognostic effect between CD20 B lymphocytes and CD8 T lymphocytes is suggested.
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http://dx.doi.org/10.1038/s41598-019-56441-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934737PMC
December 2019

Sclerosing sialadenitis of the submandibular gland is rarely an immunoglobulin G4-related disease in the Finnish population.

Mod Pathol 2020 04 3;33(4):551-559. Epub 2019 Nov 3.

Department of Otorhinolaryngology-Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, PO Box 263, FI-00029, Helsinki, Finland.

Chronic sclerosing sialadenitis may represent one of many manifestations of an immunoglobulin G4-related disease. However, existing studies typically consist of small patient cohorts rarely conducted in Western populations. The clinical behavior of chronic sclerosing sialadenitis, including follow-up data, warrants further study. Thus, we aimed to determine whether chronic sclerosing sialadenitis always presents as IgG4-related disease or associates with autoimmune diseases and to determine which additional examinations patients may require. Between 2000 and 2017, 51 patients undergoing submandibular gland resection within the Helsinki University Hospital area were diagnosed with chronic sclerosing sialadenitis. We re-evaluated all specimens and performed immunostaining for IgG4. IgG and CD31 stainings were performed for IgG4-positive specimens. IgG4-related disease diagnosis was defined by the Boston consensus statement criteria. We revised clinical data, distributing a follow-up questionnaire to patients to register symptoms of IgG4-related disease or autoimmune disease during follow-up. The chronic sclerosing sialadenitis criteria were fulfilled in 34 patients, whereby 17 were diagnosed as non-sclerosing chronic sialadenitis. In 19 cases, a sialolith associated with a salivary gland lesion. In total, 12 of 51 cases were recognized as IgG4-positive, while two met the criteria for IgG4-related disease. These two cases belonged to the non-sclerosing chronic sialadenitis group, and both involved other organs. The histopathological features between chronic sclerosing sialadenitis and non-sclerosing chronic sialadenitis overlapped regarding the degree of fibrosis and inflammatory infiltrates. In the Finnish population, chronic sclerosing sialadenitis of the submandibular gland does not appear to present as IgG4-related disease. Non-sclerosing chronic sialadenitis can associate with IgG4-related disease. A histopathological distinction between chronic sclerosing sialadenitis and non-sclerosing chronic sialadenitis is not always unequivocal and the presence of a sialolith does not exclude IgG4-positivity. Therefore, immunostaining for IgG4 should be performed when dense plasma cell infiltration is present in either non-sclerosing chronic sialadenitis or chronic sclerosing sialadenitis.
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http://dx.doi.org/10.1038/s41379-019-0395-5DOI Listing
April 2020

High tissue MMP14 expression predicts worse survival in gastric cancer, particularly with a low PROX1.

Cancer Med 2019 11 27;8(16):6995-7005. Epub 2019 Sep 27.

Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Matrix metalloproteinase 14 (MMP14), a membrane-associated matrix metalloproteinase, has been shown to influence the invasion and metastasis of several solid tumors. Prospero homeobox protein 1 (PROX1), involved in the development and cell fate determination, is also expressed in malignant diseases functioning either as a tumor-suppressing or oncogenic factor. In certain cancers PROX1 appears to transcriptionally suppress MMP14 expression. This study, therefore, aimed to explore the association between MMP14 and PROX1 and understand their potential as prognostic biomarkers in gastric cancer. The cohort consisted of 313 individuals operated for gastric adenocarcinoma between 2000 and 2009 in the Department of Surgery, Helsinki University Hospital. MMP14 and PROX1 expressions were studied using immunohistochemistry in the patient sample and using immunoblotting and immunofluorescence in gastric cancer cell lines. We generated survival curves using the Kaplan-Meier method, determining significance via the log-rank test. A high MMP14 expression associated with being ≥67 years (P = .041), while a positive nuclear PROX1 expression associated with tumors of a diffuse histological type (P = .041) and a high cytoplasmic PROX1 expression (P < .001). Five-year disease-specific survival among patients with a high MMP14 expression was 35.9% (95% confidence interval [CI] 24.9-46.9), compared to 45.3% (95% CI 38.0-52.6) for patients with a low MMP14 (P = .030). Survival was worse specifically among those with a high MMP14 and absent nuclear PROX1 expression (hazard ratio [HR] 1.65; 95% CI 1.09-2.51; P = .019). Thus, this study confirms that a high MMP14 expression predicts a worse survival in gastric cancer, revealing for the first time that survival is particularly worse when PROX1 is low.
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http://dx.doi.org/10.1002/cam4.2576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853825PMC
November 2019

Evaluation of toll-like receptors as prognostic biomarkers in gastric cancer: high tissue TLR5 predicts a better outcome.

Sci Rep 2019 08 29;9(1):12553. Epub 2019 Aug 29.

Translational Cancer Medicine Research Programme, University of Helsinki, Helsinki, Finland.

Toll-like receptors (TLRs), key proteins in innate immunity, appear to contribute to the inflammatory environment in carcinogenesis. Thus, we aimed to evaluate the tissue expressions of TLR1, TLR2, TLR4, TLR5, TLR7, and TLR9 as potential prognostic biomarkers in gastric cancer. We applied immunohistochemistry to study tissue samples from 313 patients operated on for gastric adenocarcinoma between 2000 and 2009 at the Department of Surgery, Helsinki University Hospital, Finland. A high expression of each TLR studied associated with the high expression of each other and with the intestinal-type histology (p < 0.001 for all). Five-year disease-specific survival among patients with a high TLR5 was 53.4% (95% confidence interval [CI] 43.4-63.4), whereas among patients with a low TLR5 it was 37.6% (95% CI 30.0-45.2; p = 0.014). A high TLR5 expression functioned as a marker of a better prognosis, particularly among those with a stage II disease (hazard ratio [HR] 0.33; 0.13-0.83; p = 0.019) or an intestinal-type cancer (HR 0.58; 95% CI 0.34-0.98; p = 0.043). In this study we show, for the first time, that a high TLR5 tissue expression may identify gastric cancer patients with a better prognosis, particularly among those with a stage II disease or an intestinal-type cancer.
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http://dx.doi.org/10.1038/s41598-019-49111-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715705PMC
August 2019

L1TD1 - a prognostic marker for colon cancer.

BMC Cancer 2019 Jul 23;19(1):727. Epub 2019 Jul 23.

Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.

Background: Prognostic markers specific to a particular cancer type can assist in the evaluation of survival probability of patients and help clinicians to assess the available treatment modalities.

Methods: Gene expression data was analyzed from three independent colon cancer microarray gene expression data sets (N = 1052). Survival analysis was performed for the three data sets, stratified by the expression level of the LINE-1 type transposase domain containing 1 (L1TD1). Correlation analysis was performed to investigate the role of the interactome of L1TD1 in colon cancer patients.

Results: We found L1TD1 as a novel positive prognostic marker for colon cancer. Increased expression of L1TD1 associated with longer disease-free survival in all the three data sets. Our results were in contrast to a previous study on medulloblastoma, where high expression of L1TD1 was linked with poor prognosis. Notably, in medulloblastoma L1TD1 was co-expressed with its interaction partners, whereas our analysis revealed lack of co-expression of L1TD1 with its interaction partners in colon cancer.

Conclusions: Our results identify increased expression of L1TD1 as a prognostic marker predicting longer disease-free survival in colon cancer patients.
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http://dx.doi.org/10.1186/s12885-019-5952-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651905PMC
July 2019

Toll-like receptor 1 predicts favorable prognosis in pancreatic cancer.

PLoS One 2019 17;14(7):e0219245. Epub 2019 Jul 17.

Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Background: The link between inflammation and carcinogenesis is indisputable. In trying to understand key factors at play, cancer research has developed an interest in the toll-like receptors (TLRs), which have shown signs of having prognostic value in various adenocarcinomas. We began investigating the expression of toll-like receptors 1, 3, 5, 7, and 9 to evaluate their prognostic value of patients with pancreatic ductal adenocarcinoma (PDAC).

Methods: We collected tumor biopsies from 154 stage I-III PDAC patients surgically treated at Helsinki University Hospital between 2002 and 2011, excluding patients undergoing neoadjuvant therapy. We used tissue microarray slides and immunohistochemistry to assess expression of TLRs 1, 3, 5, 7, and 9 in PDAC tissue. Immunopositivity scores and clinicopathological characteristics were subjected to Fisher's exact test or the linear-by-linear association test. For the survival analysis, we applied the Kaplan-Meier method and log-rank test, and the Cox regression proportional hazard model served for univariate and multivariate analyses.

Results: Strong TLR1 expression was observable in 60 (39%), strong TLR3 in 48 (31%), strong TLR5 in 58 (38%), strong TLR7 in 14 (9%), and strong TLR9 in 22 (14%) patients. The multivariate analysis showed strong TLR1 expression to associate with better survival than moderate, low, or negative expression (HR = 0.68; 95% CI 0.47-0.99; p = 0.044). Additionally, those few patients with tumors negative for TLR1, TLR3, TLR7, or TLR9 fared poorly (HR = 2.41; 95% CI 1.31-4.43; p = 0.005; n = 13).

Conclusion: Strong TLR1 expression suggested better prognosis in PDAC patients, whereas negative expression of TLR1, TLR3, TLR7, or TLR9 was a sign of poor prognosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0219245PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636725PMC
March 2020

Assessment of Tumor-infiltrating Lymphocytes Predicts the Behavior of Early-stage Oral Tongue Cancer.

Am J Surg Pathol 2019 10;43(10):1392-1396

Departments of Pathology.

Tumor-infiltrating lymphocytes (TILs) have shown a promising prognostic value in many epithelial cancers. We sought to assess the prognostic value of TILs in a multicenter cohort of early oral tongue squamous cell carcinoma (OTSCC). The percentage of TILs was assessed on the surgical resection slides stained with hematoxylin and eosin. The assessment of TILs was performed in the stromal compartment and in the intraepithelial compartment (at the invasive front and at the center of the tumor). We followed the method that was described recently by the International Immuno-Oncology Biomarker Working Group for the assessment of TILs. A total of 308 cases from the 5 Finnish university hospitals and from A.C. Camargo Cancer Center, São Paulo, Brazil, were included. We found a promising prognostic value for stromal TILs at the invasive front in the multivariable analysis with a hazard ratio of 2.61 (95% confidence interval [CI], 1.77-3.83; P<0.001) for overall survival, 1.99 (95% CI, 1.07-3.69; P=0.040) for disease-specific survival, and 1.94 (95% CI, 1.14-3.29; P=0.020) for disease-free survival. In conclusion, evaluation of TILs is simple and can aid in identifying the high-risk cases of early OTSCC. The method introduced by the International Immuno-Oncology Biomarker Working Group can be used for standardized determination of TILs in early OTSCC.
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http://dx.doi.org/10.1097/PAS.0000000000001323DOI Listing
October 2019